Methods of synthesizing cannabigergol, cannabigerolic acid, and analogs thereof

ABSTRACT

Disclosed are methods for preparing cannabigerol (CBG) or a CBG analog, embodiments of the method comprising providing a compound (I); combining the compound (I) with geraniol and a solvent to form a reaction mixture; and combining the reaction mixture with an acid catalyst to form a product mixture comprising the CBG or the CBG homolog. The method may further comprise separating the CBG or the CBG analog from the product mixture and may further comprise purifying the CBG or CBG analog. Methods for preparing cannabigerolic acid (CBGA) or a cannabigerolic acid analog are also disclosed. The present disclosure also provides highly purity CBG, CBGA, and analogs thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of Ser. No. 17/699,748,filed Mar. 21, 2022, titled, “METHODS OF SYNTHESIZING CANNBIGEROL,CANNABIGEROLIC ACID, AND ANALOGS THEREOF, which is a continuationapplication of Ser. No. 17/495,058, filed on Oct. 6, 2021, titled,“METHODS OF SYNTHESIZING CANNBIGEROL, CANNABIGEROLIC ACID, AND ANALOGSTHEREOF, which is a continuation application of InternationalApplication No. PCT/CA2021/050651, filed on May 11, 2021, titled,“METHODS OF SYNTHESIZING CANNBIGEROL, CANNABIGEROLIC ACID, AND ANALOGSTHEREOF,” which claims the benefit of and priority to U.S. ProvisionalPatent Application Ser. No. 63/023,400, filed on May 12, 2020, of whichare hereby incorporated by reference in their entirety.

TECHNICAL FIELD

The present disclosure generally relates to methods of synthesizingcannabigerol (CBG), cannabigerolic acid (CBGA), and analogs thereof,including compositions having enhanced concentrations of thesecompounds.

BACKGROUND

Cannabinoids are often defined in pharmacological terms as a class ofcompounds that exceed threshold-binding affinities for specificreceptors found in central nervous system tissues and/or peripheraltissues. The interactions between cannabinoids and their receptors areunder active investigation because the resultant effects aredemonstrably important both in medicinal and reactional contexts.

The length of the alkyl side chain on the resorcinol moiety of certaincannabinoids has been shown to impact biological activity. For example,studies have shown that Δ⁹-tetrahydrocannabinol (Δ⁹-THC) requires aminimum of a three-carbon chain (i.e. tetrahydrocannabivarin; THCV) forcannabinoid receptor CB1 binding. Binding affinity increases with sidechain length to a peak affinity at an eight-carbon chain. It has beenreported that seven-carbon alkyl chain homologs of cannabidiol (CBD) andΔ⁹-THC, respectively named cannabidiphorol (CBDP) andtetrahydrocannabiphorol (THCP), can be isolated from cannabis plantmaterial in very small quantities (<1 mg in 10 g of cannabis plantmaterial).

Cannabigerol (CBG) is a non-psychoactive cannabinoid that displaysnumerous potential health benefits, including the following: functioningas a neuroprotectant; antioxidant properties; aiding with skin ailmentsas an antibacterial and antifungal agent; appetite stimulation;treatment of gastrointestinal disorders; inflammation reduction; andlowering intraocular pressure, which may benefit glaucoma patients. CBGmay also be used for recreational purposes.

The acidic derivative of CBG, cannabigerolic acid (CBGA), plays a vitalrole in the biochemistry of the cannabis plant. CBGA is a criticalprecursor in the formation of cannabinoids such astetrahydrocannabinolic acid A (THCA), cannabidiolic acid (CBDA),cannabichromenic acid (CBCA), and CBG.

Despite wide-ranging potential applications, CBG and CBGA, and analogsthereof, are not currently used at scale. CBG and CBGA are typicallyfound in low concentrations in cannabis plant material, extracts, anddistillates and/or the like. Separating CBG or CBGA from suchcompositions can pose significant challenges as CBG has similarproperties and characteristics (e.g. solubility and/or affinity profile)to a number of other cannabinoids. Similarly, CBG can be difficult toseparate from reaction mixtures. Therefore, isolation of CBG from acannabis plant is a challenging, costly, and time-consuming process,rendering large-scale quantities of CBG or CBGA effectivelyinaccessible.

Accordingly, alternate methods for producing and obtaining CBG, CBGA andanalogs thereof are desirable, particularly in large quantities.

SUMMARY

The present disclosure relates to methods of synthesizing cannabigerol(CBG), cannabigerolic acid (CBGA), and analogs thereof.

In one aspect, the present disclosure relates to a method for preparingCBG or a CBG analog, the method comprising: providing a compound (I) ofthe following structure:

wherein R¹ is hydrogen, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl,(OCH₂CH₂)₀₋₆O(C₁-C₈ alkyl), (C₀-C₄ alkyl)-NR^(2a)R^(2b), (C₀-C₄alkyl)-aryl, (C₀-C₄ alkyl)-heteroaryl, (C₀-C₄ alkyl)-cycloalkyl, or(C₀-C₄ alkyl)-heterocycloalkyl, wherein R^(2a) and R^(2b) are eachindependently hydrogen or C₁-C₆ alkyl; combining the compound (I) withgeraniol and a solvent to form a reaction mixture; and combining thereaction mixture with an acid catalyst to form a product mixturecomprising the CBG or the CBG analog. In select embodiments, R¹ is C₃H₇,C₅H₁₁ or C₇H₁₅.

In an embodiment, the methods of the present disclosure further comprisea step of separating the CBG or the CBG analog from the product mixtureobtained by the methods described herein.

In an embodiment, the methods of the present disclosure further comprisea step of purifying the CBG or the CBG analog provided by the methodsdescribed herein.

In another aspect, the present disclosure relates to a CBG or CBG analogcomposition obtained by the methods described herein.

In another aspect, the present disclosure relates to a high purity CBGor CBG analog obtained by the methods as described herein. In selectembodiments, the high purity CBG or CBG analog has a purity of at least90%, more particularly at least 95%, or even more particularly at least99%.

In select embodiments of the present disclosure, the CBG analog iscannabigerovarin (CBGV).

In select embodiments of the present disclosure, the CBG analog iscannabigerophorol (CBGP).

In another aspect, the present disclosure relates to a method forpreparing CBGA or a CBGA analog, the method comprising: combining CBG ora CBG analog with methylmagnesium carbonate (MMC) and a solvent toprovide a product mixture comprising the CBGA or the CBGA analog.

In another aspect, the present disclosure relates to a method forpreparing CBGA or a CBGA analog, the method comprising: providing acompound (II) of the following structure:

wherein R¹ is hydrogen, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl,(OCH₂CH₂)₀₋₆O(C₁-C₈ alkyl), (C₀-C₄ alkyl)-NR^(2a)R^(2b), (C₀-C₄alkyl)-aryl, (C₀-C₄ alkyl)-heteroaryl, (C₀-C₄ alkyl)-cycloalkyl, or(C₀-C₄ alkyl)-heterocycloalkyl, wherein R^(2a) and R^(2b) are eachindependently hydrogen or C₁-C₆ alkyl; combining the compound (II) withgeraniol and a solvent to provide a reaction mixture; combining thereaction mixture with an acid catalyst to provide a first productmixture; and combining at least a portion of the first product mixturewith one or more mild hydrolysis reagents to provide a second productmixture comprising the CBGA or CBGA analog. In select embodiments, R¹ isC₃H₇, C₅H₁₁ or C₇H₁₅.

In another aspect, the present disclosure relates to a CBGA or CBGAanalog composition obtained by the methods as described herein.

In another aspect, the present disclosure relates to a high purity CBGAor CBG analog obtained by the methods as described herein. In selectembodiments, the high purity CBGA or CBGA analog has a purity of atleast 90%.

Other aspects and features of the present disclosure will becomeapparent to those ordinarily skilled in the art upon review of thefollowing description of specific embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a schematic of a method in accordance with the presentdisclosure where CBG or a CBG analog is prepared and can be isolated inhigh purity.

FIG. 2 shows a schematic of a method in accordance with the presentdisclosure where CBGA or a CBGA analog is prepared from CBG or a CBGanalog and can be isolated in high purity.

FIG. 3 shows a schematic of an alternate method of preparing CBGA or aCBGA analog in accordance with the present disclosure.

FIG. 4 shows a high performance liquid chromatography (HPLC)chromatogram of high purity CBG provided by the methods of the presentdisclosure.

FIGS. 5A-5E show HPLC chromatograms of CBG prepared and purified by amethod of the present disclosure and recovered reactants. FIG. 5A showsa chromatogram of a product mixture comprising about 20% CBG provided bythe methods disclosed herein. FIG. 5B shows a chromatogram of thedistillate comprising about 40% CBG and obtained from the productmixture. FIGS. 5C and 5D show chromatograms of recovered geraniol andolivetol, respectively. FIG. 5E shows a chromatogram of CBG crystalsafter separation from the product mixture and crystallization.

FIG. 6 shows HPLC with diode array detector (HPLC-DAD) of the reactionmixture at the end of the set of reaction conditions provided by amethod of the present disclosure. The reaction mixture comprises about90% CBGA and about 10% CBG.

DETAILED DESCRIPTION

An important aspect of the cannabis industry is having cost-effectiveaccess to sufficient quantities of cannabinoids, including those lessabundant in cannabis plant material.

In many instances, it may be desirable to isolate large quantities ofcannabinoids that are present in low quantities in cannabis plantmaterial or cannabis extracts. Further, it may be desirable to preparecannabinoid analogs, as some cannabinoid homologs have been shown toimprove binding affinity to CB1 receptors.

The present disclosure relates to methods for synthesizing cannabigerol(CBG), cannabigerolic acid (CBGA), and analogs thereof. The methodsdisclosed herein may be used to provide compositions enriched in CBG,CBGA, or analogs thereof, which may then be further purified to yieldhigh purity compositions or high purity cannabinoids (e.g. CBG, CBGA, oranalogs thereof).

An advantageous aspect of the synthetic methods provided herein is thatCBG and CBGA can be prepared in large quantities that would otherwisenot be accessible from extraction of cannabis plant material. A furtheradvantage of the present disclosure is the provision of CBG and CBGAanalogs, which may not be naturally occurring. Without being bound byany particular theory, analogs of CBG or CBGA may be of interest fortheir properties with respect to binding affinities to cannabinoidreceptors (e.g. CB1 and/or CB2).

As used herein, the term “analog” is intended to refer to compounds thatdiffer at the meta-position with respect to the hydroxyl groups of theresorcinol moiety. In select embodiments of the present disclosure, thesubstituent may be any of the R¹ substituents defined herein. In thecontext of the present disclosure, analogs include homologs. The term“homolog” as used herein refers to a group or series of compounds thatdiffer only with respect to the number of repeating units in the alkylchain on the resorcinol moiety located at the meta-position with respectto the hydroxyl groups. More specifically, homologs of the presentdisclosure include alkyl chains on the resorcinol moiety of the formula—(CH₂)₀₋₁₁CH₃ with the repeating unit in the alkyl chain being themethylene (—CH₂—) unit. For example, CBG has a five-carbon alkyl chainlength whereas the homologs cannabigerovarin (CBGV; sometimes alsoreferred to as cannabigerovarin) and cannabigerophorol (CBGP) havethree-carbon and seven-carbon alkyl chain lengths, respectively. Theterm homolog is not limited to homologs of naturally occurringcannabinoids and includes homologs of semi-synthetic and cannabinoidderivatives.

As used herein, the term “cannabinoid” refers to a chemical compoundbelonging to a class of secondary compounds commonly found in plants ofgenus cannabis, but also encompasses synthetic and semi-syntheticcannabinoids and any enantiomers thereof.

In select embodiments of the present disclosure, the cannabinoid is acompound found in a plant, e.g., a plant of genus cannabis, and issometimes referred to as a phytocannabinoid. In select embodiments ofthe present disclosure, the cannabinoid is a compound found in a mammal,sometimes called an endocannabinoid. In select embodiments of thepresent disclosure, the cannabinoid is made in a laboratory setting,sometimes called a synthetic cannabinoid. In select embodiments of thepresent disclosure, the cannabinoid is derived or obtained from anatural source (e.g. plant) but is subsequently modified or derivatizedin one or more different ways in a laboratory setting, sometimes calleda semi-synthetic cannabinoid.

A notable cannabinoid of the phytocannabinoids is tetrahydrocannabinol(THC), the primary psychoactive compound in cannabis. Cannabidiol (CBD)is another cannabinoid that is a major constituent of thephytocannabinoids. There are at least 113 different cannabinoidsisolated from cannabis, exhibiting varied effects.

Synthetic cannabinoids and semi-synthetic cannabinoids encompass avariety of distinct chemical classes, for example and withoutlimitation: the classical cannabinoids structurally related to THC, thenon-classical cannabinoids (cannabimimetics).

In many cases, a cannabinoid can be identified because its chemical namewill include the text string “*cannabi*”. However, there are a number ofcannabinoids that do not use this nomenclature, such as for examplethose described herein.

Within the context of this disclosure, where reference is made to aparticular cannabinoid, each of the acid and/or decarboxylated forms arecontemplated as both single molecules and mixtures. As well, any and allisomeric, enantiomeric, or optically active derivatives are alsoencompassed. In particular, where appropriate, reference to a particularcannabinoid incudes both the “A Form” and the “B Form”. For example, itis known that THCA has two isomers, THCA-A in which the carboxylic acidgroup is in the 1 position between the hydroxyl group and the carbonchain (A Form) and THCA-B in which the carboxylic acid group is in the 3position following the carbon chain (B Form).

The present disclosure relates specifically to the cannabinoids CBG,CBGA and analogs thereof, each of CBG and CBGA having the followingstructural formula:

In one aspect, the present disclosure provides a method for preparingCBG or a CBG analog, the method comprising: providing a compound (I) ofthe following structure:

wherein R¹ is hydrogen, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl,(OCH₂CH₂)₀₋₆O(C₁-C₈ alkyl), (C₀-C₄ alkyl)-NR^(2a)R^(2b), (C₀-C₄alkyl)-aryl, (C₀-C₄ alkyl)-heteroaryl, (C₀-C₄ alkyl)-cycloalkyl, or(C₀-C₄ alkyl)-heterocycloalkyl, wherein R^(2a) and R^(2b) are eachindependently hydrogen or C₁-C₆ alkyl; combining the compound (I) withgeraniol and a solvent to form a reaction mixture; and combining thereaction mixture with an acid catalyst to form a product mixturecomprising the CBG or the CBG analog.

As used herein, the term “alkyl” refers to a saturated hydrocarbonhaving a designated number of carbon atoms, such as 1 to 12 carbons(i.e., inclusive of 1 and 12), 1 to 8 carbons, 1 to 6 carbons, 1 to 3carbons, or 1, 2, 3, 4, 5, 6, 7 or 8 carbons. The alkyl group may bestraight or branched and depending on context, may be a monovalentradical or a divalent radical (i.e., an alkylene group). For example,the moiety “—(C₁-C₆ alkyl)-O—” signifies connection of an oxygen throughan alkylene bridge having from 1 to 6 carbons. Examples of “alkyl”include, for example, methyl, ethyl, propyl, isopropyl, butyl, pentyl,hexyl, and heptyl.

The term “alkenyl” as used herein, refers to an unsaturated hydrocarboncontaining from 2 to 12 carbons (i.e., inclusive of 2 and 12), 2 to 8carbons, 2 to 6 carbons, or 2, 3, 4, 5 or 6, unless otherwise specified,and containing at least one carbon-carbon double bond. Representativeexamples of alkenyl include, but are not limited to, ethenyl,2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl,2-heptenyl, and 2-methyl-1-heptenyl.

The term “alkynyl” as used herein, refers to an unsaturated hydrocarboncontaining from 2 to 12 carbons (i.e., inclusive of 2 and 12), 2 to 8carbons, 2 to 6 carbons, or 2, 3, 4, 5 or 6 unless otherwise specified,and containing at least one carbon-carbon triple bond. Alkynyl group maybe straight or branched and depending on context, may be a monovalentradical or a divalent radical (i.e., an alkynylene group).Representative examples of alkynyl include, but are not limited to,acetylenyl, 1-propynyl, 2-propynyl, and 3-butynyl.

The term “aryl” represents an aromatic ring system having a single ring(e.g., phenyl) which is optionally fused to other aromatic hydrocarbonrings or non-aromatic hydrocarbon or heterocycle rings. “Aryl” includesring systems having multiple condensed rings and in which at least oneis carbocyclic and aromatic, (e.g., 1,2,3,4-tetrahydronaphthyl,naphthyl). Examples of aryl groups include phenyl, 1-naphthyl,2-naphthyl, indanyl, indenyl, and dihydronaphthyl. “Aryl” also includesring systems having a first carbocyclic, aromatic ring fused to anonaromatic heterocycle, for example, 1H-2,3-dihydrobenzofuranyl. Thearyl groups herein can be substituted in one or more substitutablepositions, or not.

The term “heteroaryl” refers to an aromatic ring system containing atleast one aromatic heteroatom selected from nitrogen, oxygen and sulfurin an aromatic ring. Most commonly, the heteroaryl groups will have 1,2, 3, or 4 heteroatoms. The heteroaryl may be fused to one or morenon-aromatic rings, for example, cycloalkyl or heterocycloalkyl rings,wherein the cycloalkyl and heterocycloalkyl rings are described herein.Examples of heteroaryl groups include, for example, pyridyl,pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl, pyridazinyl,pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl,phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl,indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl,furanyl, thienyl, and pyrrolyl. The heteroaryl groups herein may besubstituted in one or more substitutable positions, or not.

The term “heterocycloalkyl” refers to a non-aromatic ring or ring systemcontaining at least one heteroatom that is preferably selected fromnitrogen, oxygen and sulfur, wherein said heteroatom is in anon-aromatic ring. The heterocycloalkyl may have 1, 2, 3 or 4heteroatoms. The heterocycloalkyl may be saturated (i.e., aheterocycloalkyl) or partially unsaturated (i.e., a heterocycloalkenyl).Heterocycloalkyl includes monocyclic groups of three to eight annularatoms as well as bicyclic and polycyclic ring systems, including bridgedand fused systems, wherein each ring includes three to eight annularatoms. The heterocycloalkyl ring is optionally fused to otherheterocycloalkyl rings and/or non-aromatic hydrocarbon rings. In certainembodiments, the heterocycloalkyl groups have from 3 to 7 members in asingle ring. In other embodiments, heterocycloalkyl groups have 5 or 6members in a single ring. In some embodiments, the heterocycloalkylgroups have 3, 4, 5, 6 or 7 members in a single ring. Examples ofheterocycloalkyl groups include, for example, azabicyclo[2.2.2]octyl (ineach case also “quinuclidinyl” or a quinuclidine derivative),azabicyclo[3.2.1]octyl, 2,5-diazabicyclo[2.2.1]heptyl, morpholinyl,thiomorpholinyl, piperazinyl, pyrrolidinyl, azepanyl, azetidinyl,pyrrolinyl, tetrahydropyranyl, piperidinyl, tetrahydrofuranyl,3,4-dihydroisoquinolin-2(1H)-yl, γ-butyrolactonyl (i.e., anoxo-substituted tetrahydrofuranyl), γ-butryolactamyl (i.e., anoxo-substituted pyrrolidine), azetidinyl, thiomorpholinyl,imidazolidonyl, isoindolindionyl, piperazinonyl. The heterocycloalkylgroups herein may be substituted in one or more substitutable positions,or not.

The methods herein for preparing CBG or a CBG analog comprise combiningthe compound (I) with geraniol and a solvent to form a reaction mixture.

As used herein, the term “solvent” is meant to refer to a substance thatdissolves a solute (e.g. one or more reagents). In select embodiments,the solvent is a liquid. In an embodiment, the solvent is a hydrocarbonor halogenated hydrocarbon solvent. In exemplary embodiments of thepresent disclosure, the solvent is chloroform, heptane, tert-butylmethylether (TBME), diethyl ether, dichloromethane, dichloroethane,trifluorotoluene, hexane, cyclohexane, pentane, or any combinationthereof. In a particular embodiment, the solvent is chloroform.

Geraniol is a monoterpenoid and an alcohol that is soluble in commonorganic solvents and consists of the following form:

The combining of the compound (I) with geraniol and a solvent may bedone in any order to form the reaction mixture. For example, thecombining may comprise adding the compound (I) to the geraniol andadding the solvent thereto. In other embodiments, the compound (I) andthe geraniol may each be in the solvent prior to combining. Thecombining may be done by any suitable means such that the compound (I)and geraniol are brought together. In an embodiment, the combininginvolves mixing such as, but not limited to, stirring in a reactionflask or vessel.

In select embodiments, the combining of the compound (I) with geranioland a solvent comprises a compound (I):geraniol molar ratio of betweenabout 10:1 and about 1:10, more particularly between about 5:1 and about1:5, and more particularly still between about 1:1.5 and about 1:3.5. Asthe skilled person will appreciate, the term “molar ratio” refers to theproportion of the reagents on a molar basis. In an embodiment, thecompound (I):geraniol molar ratio is between about 1:1.5 to about 1:2.In an embodiment, the compound (I):geraniol molar ratio is about 1:1.5,about 1:1.6, about 1:1.7, about 1:1.8, about 1:1.9, about 1:2.0 about1:2.1, about 1:2.2, about 1:2.3, about 1:2.4, about 1:2.5, about 1:2.6about 1:2.7 about 1:2.8, about 1:2.9, about 1:3.0, about 1:3.1, about1:3.2, about 1:3.3, about 1:3.4, or about 1:3.5. In a particularembodiment, the compound (I):geraniol molar ratio is about 1:1.7.

The methods herein for preparing CBG or a CBG analog further comprisecombining the reaction mixture above with an acid catalyst under a setof reaction conditions to form a product mixture comprising the CBG orthe CBG analog.

As used herein, the term “acid catalyst” is intended to refer to an acidthat increases the rate of chemical reaction without itself undergoingany change. In select embodiments of the present disclosure, the acidcatalyst is p-toluenesulfonic acid monohydrate, camphorsulfonic acid,acidic alumina, montmorillonite K10, BF₃.Et₂O, iron (III) perchloratehydrate, or a combination thereof.

In a particular embodiment, the acid catalyst is p-Toluenesulfonic acidmonohydrate, an organic compound of the following form:

In another particular embodiment, the acid catalyst is camphorsulfonicacid, an organosulfur compound of the following form:

Both p-toluenesulfonic acid monohydrate and camphorsulfonic acid aresoluble in water, alcohols, and other organic solvents. Without beingbound by any particular theory, the acid catalyst may promote a reactionbetween the compound (I) and geraniol under the reaction conditionsdescribed herein to provide CBG or a CBG analog.

The combining may be done by any suitable means such that the reactionmixture and the acid catalyst are brought together. In an embodiment,the combining is by mixing. In select embodiments, the acid catalyst isadded (e.g. dropwise) to the reaction mixture. Alternatively, thereaction mixture may be added to the acid catalyst. In selectembodiments, the acid catalyst may be in a solvent, such as for examplethe solvents described herein.

In select embodiments of the present disclosure, the acid catalyst maybe used in an amount of between about 0.001 and about 10 molarequivalents with respect to the amount of the compound (I), moreparticularly between about 0.01 and about 1.0 molar equivalents withrespect to the amount of the compound (I), and more particularly stillbetween about 0.01 and about 0.5 molar equivalents with respect to theamount of the compound (I). In an embodiment, the acid catalyst may beused in an amount of between about 0.01 and about 0.1 molar equivalentswith respect to the amount of the compound (I). In an embodiment, theacid catalyst is in an amount of 0.01, 0.02, 0.03, 0.04, 0.05, 0.06,0.07, 0.08, 0.09, or 0.1 molar equivalents with respect to the compound(I).

The reaction mixture and the acid catalyst are combined under a set ofreaction conditions to form a product mixture comprising the CBG or theCBG analog. As used herein, the term “under a set of reactionconditions” is intended to refer to conditions such as temperature,pressure, and time used in the methods of the present disclosure. As theskilled person will appreciate, each of these variables may be dependentupon one or more of the others, such that changes to one may necessitatechanges to the others.

In an embodiment of the methods herein, the pressure is atmosphericpressure. In other embodiments, the pressure is a pressure belowatmospheric pressure also referred to as “reduced pressure”. In anembodiment, the reaction pressure is between about 0.1 mbar and 1000mbar, more particularly between about 0.1 mbar and 500 mbar, betweenabout 0.1 mbar and 100 mbar, or between about 0.5 mbar and 10 mbar.

In select embodiments, combining the reaction mixture with an acidcatalyst under a set of reaction conditions comprises stirring at aparticular temperature for a particular time. In an embodiment, thetemperature is between about 5° C. and about 35° C., more particularlybetween about 10° C. and about 30° C., and more particularly stillbetween about 15° C. and about 30° C. In select embodiments, thetemperature is about 10° C., about 11° C., about 12° C., about 13° C.,about 14° C., about 15° C., about 16° C., about 17° C., about 18° C.,about 19° C., about 20° C., about 21° C., about 22° C., about 23° C.,about 24° C., about 25° C., about 26° C., about 27° C., about 28° C.,about 29° C., or about 30° C. In a particular embodiment, thetemperature is room temperature, conventionally understood to be about20° C.

In an embodiment, the time is between about 30 minutes and about 72hours, more particularly between about 6 hours and about 60 hours, moreparticularly still between about 12 hours and about 48 hours. In a moreparticular embodiment, the time is between about 14 hours and about 24hours. In select embodiments, the time is about 10 hours, about 11hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours,about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20hours, about 21 hours, about 22 hours, about 23 hours, or about 25hours. In a particular embodiment, the time is about 14 hours.

In a particular embodiment, the combining of the reaction mixture andthe acid catalyst is performed at a temperature between about 15° C. andabout 30° C. and at a time between about 14 hours and about 48 hours,more particularly at about 20° C. and for about 14 hours.

The methods disclosed herein provide a product mixture that comprisesCBG or a CBG analog. As used herein, the term “product mixture” isintended to refer to a mixture that comprises CBG or the CBG analog andat least one other component that is produced by the methods disclosedherein. In select embodiments, the at least one other component may beone or more unreacted reagents. For example, the at least one othercomponent may be the acid catalyst and/or may be a reaction by-product.

In select embodiments of the present disclosure, the product mixturecomprises the CBG or the CBG analog in an amount of between about 1% w/wand about 99.99% w/w, or more particularly between about 5% w/w andabout 95%, about 10% w/w and about 75% w/w, between about 10% w/w andabout 50% w/w, or between about 15% w/w and about 40% w/w. In anembodiment, the product mixture comprises between about 1% w/w and about65% w/w, more particularly between about 10% w/w and about 35% w/w, orbetween about 15% w/w and about 25% w/w. In an embodiment, the productmixture comprises between about 5% w/w and about 25% w/w. In anembodiment, the product mixture comprises about 1.0%, about 2.5%, about5.0%, about 7.5%, about 10.0%, about 12.5%, about 15.0%, about 17.5%,about 20.0%, about 22.5%, about 25%, about 27.5%, about 30%, about32.5%, about 35%, about 37.5%, about 40%, about 42.5%, about 45%, about47.5%, about 50%, about 52.5%, about 55%, about 57.5%, about 60%, about65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%,or greater w/w CBG or CBG analog. In other embodiments, the productmixture comprises the CBG or the CBG analog in an amount of at leastabout 15% by weight, at least 20% by weight, or more. In a particularembodiment, the product mixture comprises the CBG or the CBG analog inan amount of at least about 20% by weight. By “at least about X % byweight” it is meant that of the total weight of the product mixtureprovided by the method disclosed herein, at least that “X” percentage isattributed to the weight of the CBG or CBG analog.

In select embodiments herein, R¹ is C₅H₁₁ and the product mixturecomprises CBG. In other embodiments, R¹ is C₃H₇ and the product mixturecomprises cannabigerovarin (CBGV). In other embodiments still, R¹ isC₇H₁₅ and the product mixture comprises cannabigerophorol (CBGP).

The methods for preparing CBG or a CBG analog disclosed herein mayfurther comprise a step of separating the CBG or the CBG analog from theproduct mixture. The separating may be by any suitable method or means.In select embodiments, the separating comprises one or both of achromatography step and a distillation step.

Separation by chromatography may comprise, for example, a normal phaseflash chromatography with a solvent system comprising heptane and one oftert-butyl methyl ether (TBME) or acetone. Flash chromatography is aform of chromatography that uses low to medium pressures to advance asolution through a chromatography column. The skilled person willappreciate that gravity flow or other forms of chromatography may alsobe used for the separating.

Separation by distillation may comprise, for example, a fractionaldistillation under reduced pressure. Fractional distillation separates amixture into components based on differences in vaporization points. Inselect embodiments of the present disclosure, the distillationconditions may comprise about 0.2 mbar at a temperature of between about52° C. and about 58° C. to distill unreacted geraniol; about 0.45 mbarat a temperature of between about 140° C. and about 150° C. to distillunreacted olivetol; and about 0.45 mbar at a temperature of betweenabout 160° C. and about 180° C. to distill CBG or CBG analog. Theskilled person will appreciate that other forms of distillation andother conditions may also be used to separate the CBG or CBG analog fromthe product mixture.

The methods herein for preparing CBG or a CBG analog may furthercomprise a step of purifying the CBG or CBG analog. In selectembodiments, the purifying is by crystallization. As the skilled personwill appreciate, crystallization is a process by which atoms ormolecules arrange in a highly organized structure and precipitate out ofa solution. Generally speaking, crystallization occurs from a saturatedand/or cooled solution comprising the compound of interest. In selectembodiments of the methods herein, the crystallization is in heptane.For example, the product mixture may be dissolved in heptane and cooleduntil at least some of the CBG or the CBG analog precipitates.

The methods for preparing CBG or a CBG analog may further comprise astep of recovering at least a portion of unreacted compound (I), atleast a portion of unreacted geraniol, or both. As used herein, the term“recovering” is intended to refer to a process or means of obtaining amaterial in its original form after it has been used. Non-limitingexamples of recovering at least a portion of the unreacted compound (I)are by distillation or chromatography.

The methods disclosed herein are suitable for preparing a compositioncomprising CBG or a CBG analog. In an embodiment, the CBG or CBG analogcomposition is the product mixture as described herein. In otherembodiments, the CBG or CBG analog composition is a resultantcomposition prepared by subsequent separation or purification steps. Inother embodiments, the CBG or CBG analog composition may be any of thesecompositions having additional components added thereto, such as anacceptable carrier, excipient, diluent or other additive, for examplefor pharmaceutical or recreational use of the CBG or CBG analogcomposition.

The present disclosure also provides a high purity CBG or CBG analogobtained by the methods herein. In an embodiment, the high purity CBG orCBG analog is obtained by utilizing the separating and/or purifyingsteps as described herein. As used herein, the term “high purity” isintended to refer to the extent to which the CBG or CBG analog, or theCBGA or CBGA analog described below, is free from other components, alsoreferred to as impurities. In an embodiment of the present disclosure,the high purity CBG or CBG analog has a purity of at least 75%, and moreparticularly at least 90%. In an embodiment, the high purity CBG or CBGanalog has a purity of at least 75%, at least 77.5%, at least 80%, atleast 82.5%, at least 85%, at least 87.5%, at least 90%, at least 92.5%,at least 95%, at least 97.5%, or greater. In select embodiments, thehigh purity CBG or CBG analog has a purity of at least 95%. In furtherselect embodiments, the high purity CBG or CBG analog has a purity of atleast 99%. Crystallization may provide pure CBG or CBG analogs.

In another aspect, the present disclosure provides a method forpreparing CBGA or a CBGA analog, the method comprising: combining CBG ora CBG analog with methylmagnesium carbonate (MMC) and a solvent toprovide a product mixture comprising the CBGA or the CBGA analog.

In select embodiments of the present disclosure, the CBG is a CBGdistillate, a CBG isolate, a semi-synthetic CBG, a synthetic CBG or anycombination thereof. As used herein, the term “CBG distillate” is usedto refer to a form of CBG oil produced by a distillation process, suchas distillation of a cannabis resin. As used herein, the term “CBGisolate” is used to refer to CBG isolated in pure form, such as acrystalline solid or powder. In select embodiments, the synthetic CBG orCBG analog is provided by the methods disclosed herein for preparing CBGor a CBG analog.

The CBG or CBG analog are combined with MMC under a set of reactionconditions to form a product mixture comprising the CBGA or the CBGAanalog. In select embodiments, the set of reaction conditions comprisesstirring at a particular temperature for a particular time under aninert atmosphere. As used herein, the term “inert atmosphere” isintended to refer to a nonreactive gas atmosphere, such as nitrogen,argon, or helium. In select embodiments of the methods herein, the inertatmosphere comprises argon, nitrogen, or a combination thereof. In anembodiment, the temperature is between about 40° C. and about 180° C.,more particularly between about 60° C. and about 160° C., moreparticularly still between about 100° C. and about 140° C. In anembodiment, the temperature is about 60° C., about 65° C., about 70° C.,about 75° C., about 80° C., about 85° C., about 90° C., about 95° C.,about 100° C., about 105° C., about 110° C., about 115° C., about 120°C., about 125° C., about 130° C., about 135° C., or about 140° C. In anembodiment, the time is between about 30 minutes and about 72 hours,more particularly between 1 hour and 48 hours, and more particularlystill between 2 hours and 24 hours. In an embodiment, the time is about1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours,about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10hours, about 11 hours, about 12 hours, or longer. In select embodiments,the temperature is between about 60° C. and about 160° C. and the timeis between about 0.5 hours and about 48 hours. In a particularembodiment, the temperature is about 125° C. and the time is about 2.5hours.

As described elsewhere herein, the term “solvent” refers to a substancethat dissolves a solute (e.g. one or more reagents). In selectembodiments of the methods for preparing CBGA or a CBGA analog, thesolvent is dimethylformamide. In other embodiments, the solvent may bedimethyl sulfoxide (DMSO), N,N′-dimethylpropyleneurea (DMPU), dimethylacetamide, tetrahydrofuran (THF), or propylene carbonate.

The method for preparing CBGA or a CBGA analog may further comprises astep of crystallization. In select embodiments of the methods herein,the step of crystallization comprises combining the CBGA or CBGA analogwith a solvent mixture. The solvent mixture may comprise, for exampleand without limitation, acetone and heptane.

In a further aspect, the present disclosure provides a method forpreparing CBGA or a CBGA homolog, where the method comprises: providinga compound (II) of the following structure:

wherein R¹ is hydrogen, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl,(OCH₂CH₂)₀₋₆O(C₁-C₈ alkyl), (C₀-C₄ alkyl)-NR^(2a)R^(2b), (C₀-C₄alkyl)-aryl, (C₀-C₄ alkyl)-heteroaryl, (C₀-C₄ alkyl)-cycloalkyl, or(C₀-C₄ alkyl)-heterocycloalkyl, wherein R^(2a) and R^(2b) are eachindependently hydrogen or C₁-C₆ alkyl; combining the compound (II) withgeraniol and a solvent to provide a reaction mixture; combining thereaction mixture with an acid catalyst to provide a first productmixture; and combining at least a portion of the first product mixturewith one or more mild hydrolysis reagents to provide a second productmixture comprising the CBGA or CBGA analog.

As used herein, the term “mild hydrolysis reagent” is intended to referto a reagent that promotes the conversion of an ester functional groupon a compound to a carboxylic acid functionality, without reacting withother parts of the compound.

In embodiments of the methods herein for preparing CBGA or a CBGAanalog, the combining the compound (II) with geraniol and a solvent toprovide a reaction mixture may be performed as described herein inrelation to combining the compound (I) with geraniol and a solvent toprepare CBG or a CBG analog.

In select embodiments of the methods herein, the combining of thecompound (II) with geraniol and a solvent comprises a compound(II):geraniol molar ratio of between about 10:1 and about 1:10, moreparticularly between about 5:1 and about 1:5, and more particularlystill between about 1:1.5 and about 1:3.5. In an embodiment, the acompound (II):geraniol molar ratio is between about 1:1.5 to about 1:2.In an embodiment, the compound (II):geraniol molar ratio is about 1:1.5,about 1:1.6, about 1:1.7, about 1:1.8, about 1:1.9, about 1:2.0 about1:2.1, about 1:2.2, about 1:2.3, about 1:2.4, about 1:2.5, about 1:2.6about 1:2.7 about 1:2.8, about 1:2.9, about 1:3.0, about 1:3.1, about1:3.2, about 1:3.3, about 1:3.4, or about 1:3.5. In a particularembodiment, the compound (II):geraniol molar ratio is about 1:1.7.

The step of forming the reaction mixture comprises combining thecompound (II) with geraniol and a solvent. In select embodiments of themethods for preparing CBGA or a CBGA analog, the solvent is chloroform,heptane, TBME, or a combination thereof. In a particular embodiment, thesolvent is chloroform.

The methods herein for preparing CBGA or a CBGA analog further comprisecombining the reaction mixture above with an acid catalyst under a setof reaction conditions to form a product mixture comprising the CBGA orthe CBGA analog. The combining of the reaction mixture with the acidcatalyst may be by any of the means disclosed elsewhere herein inrelation to the methods for preparing CBG or a CBG analog. In anembodiment, the acid catalyst is p-toluenesulfonic acid monohydrate,camphorsulfonic acid, or a combination thereof. In a particularembodiment, the acid catalyst is p-toluenesulfonic acid monohydrate. Inanother particular embodiment, the acid catalyst is camphorsulfonicacid.

In select embodiments of the present disclosure, the acid catalyst maybe used in an amount of between about 0.001 and about 10 molarequivalents with respect to the amount of the compound (I), moreparticularly between about 0.01 and about 1.0 molar equivalents withrespect to the amount of the compound (I), and more particularly stillbetween about 0.01 and about 0.5 molar equivalents with respect to thecompound (II). In an embodiment, the acid catalyst may be used in anamount of between about 0.01 and about 0.1 molar equivalents withrespect to the compound (II). In an embodiment, the acid catalyst is inan amount of 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, or0.1 molar equivalents with respect to the compound (II).

The reaction mixture and the acid catalyst are combined under a firstset of reaction conditions to form a first product mixture. The firstset of reaction conditions comprise a temperature, pressure and time. Asthe skilled person will appreciate, each of these variables may bedependent upon one or more of the others, such that changes to one maynecessitate changes to the others.

In an embodiment of the methods herein for preparing CBGA or a CBGAanalog, the pressure is atmospheric pressure. In other embodiments, thepressure is a pressure below atmospheric pressure also referred to as“reduced pressure”. In an embodiment, the reaction pressure is betweenabout 0.1 mbar and 1000 mbar, more particularly between about 0.1 mbarand 500 mbar, between about 0.1 mbar and 100 mbar, or between about 0.5mbar and 10 mbar.

In select embodiments, combining the reaction mixture with an acidcatalyst under a first set of reaction conditions comprises stirring ata particular temperature for a particular time. In an embodiment, thetemperature is between about 5° C. and about 35° C., more particularlybetween about 10° C. and about 30° C., and more particularly stillbetween about 15° C. and about 30° C. In select embodiments, thetemperature is about 10° C., about 11° C., about 12° C., about 13° C.,about 14° C., about 15° C., about 16° C., about 17° C., about 18° C.,about 19° C., about 20° C., about 21° C., about 22° C., about 23° C.,about 24° C., about 25° C., about 26° C., about 27° C., about 28° C.,about 29° C., or about 30° C. In a particular embodiment, thetemperature is room temperature, conventionally understood to be about20° C.

The time may be any suitable for the reaction to occur. In anembodiment, the time is between about 30 minutes and about 72 hours,more particularly between about 6 hours and about 60 hours, moreparticularly still between about 12 hours and about 48 hours. In a moreparticular embodiment, the time is between about 10 hours, about 11hours, about 12 hours, about 13 hours, about 14 hours and about 24hours. In select embodiments, the time is about 14 hours, about 15hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours,about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about25 hours. In a particular embodiment, the time is about 14 hours.

In select embodiments of the methods for preparing CBGA or a CBGAanalog, the temperature is between about 15° C. and about 30° C. and thetime is between about 12 hours and about 48 hours, more particularly atabout 20° C. and for about 14 hours.

The methods herein for preparing CBGA or a CBGA analog further comprisea step of combining at least a portion of the first product mixture withone or more mild hydrolysis reagents under a second set of reactionconditions to provide a second product mixture comprising the CBGA orCBGA analog. In select embodiments, this step comprises (a) combiningthe first product mixture with thiophenol and cesium carbonate, and (b)adding dilute hydrochloric acid. The skilled person will appreciate thatother mild hydrolysis reagents may be used to convert the ester moietyto a carboxylic acid.

The first product mixture and the one or more mild hydrolysis reagentsare combined under a second set of reaction conditions. In selectembodiments, the second set of reaction conditions comprises stirring ata particular temperature for a particular time. In an embodiment, thetemperature is between about 40° C. and about 180° C., more particularlybetween about 60° C. and about 160° C., more particularly still betweenabout 100° C. and about 140° C. In an embodiment, the temperature isabout 60° C., about 65° C., about 70° C., about 75° C., about 80° C.,about 85° C., about 90° C., about 95° C., about 100° C., about 105° C.,about 110° C., about 115° C., about 120° C., about 125° C., about 130°C., about 135° C., or about 140° C. In an embodiment, the time isbetween about 30 minutes and about 72 hours, more particularly between 1hour and 48 hours, and more particularly still between 2 hours and 24hours. In an embodiment, the time is about 1 hour, about 2 hours, about3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours,about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12hours, or longer. In a particular embodiment, the temperature is betweenabout 60° C. and 160° C. and the time is between about 0.5 and 48 hours.

The methods herein for preparing CBGA or a CBGA analog may furthercomprise separating the CBGA or the CBGA analog from the second productmixture. In select embodiments, the separating comprises one or both ofa chromatography step and a fractional distillation step as describedelsewhere herein for the separation of CBG or CBGA analogs.

The methods herein for preparing CBGA or a CBGA analog may furthercomprise purifying the CBGA or the CBGA analog. In select embodiments,the purifying is by crystallization as described elsewhere herein forthe separation of CBG or CBGA analogs.

The methods for preparing CBGA or a CBGA analog may further comprise astep of recovering at least a portion of unreacted compound (II), atleast a portion of unreacted geraniol, or both. As used herein, the term“recovering” is intended to refer to a process or means of obtaining amaterial in its original form after it has been used. In selectembodiments, the step of recovering compound (II) is as describedelsewhere herein for the recovery of compound (I).

The methods disclosed herein are suitable for preparing a compositioncomprising CBGA or a CBGA analog. In an embodiment, the CBGA or CBGAanalog composition is the product mixture as described herein. In otherembodiments, the CBGA or CBGA analog composition is a resultantcomposition from subsequent separation or purification steps. In otherembodiments, the CBGA or CBGA analog composition may be any of thesecompositions having additional components added thereto, such as anacceptable carrier, excipient, diluent or other additive, for examplefor pharmaceutical or recreational use of the CBG or CBG analogcomposition.

The present disclosure also provides a high purity CBGA or CBGA analogobtained by the methods disclosed herein. In an embodiment, the highpurity CBGA or CBGA analog is obtained by utilizing the separatingand/or purifying steps as described herein. In select embodiments, thehigh purity CBGA or CBGA analog has a purity of at least 75%, and moreparticularly at least 90%. In an embodiment, the high purity CBGA orCBGA analog has a purity of at least 75%, at least 77.5%, at least 80%,at least 82.5%, at least 85%, at least 87.5%, at least 90%, at least92.5%, at least 95%, at least 97.5%, or greater. In select embodiments,the high purity CBGA or CBGA analog has a purity of at least 95%. Infurther select embodiments, the high purity CBG or CBG analog has apurity of at least 99%. Crystallization may provide pure CBG or CBGanalogs.

Embodiments of the present disclosure will now be described by referenceto FIG. 1 to FIG. 3 , which show representations of the methods forisolating CBG, CBGA and analogs thereof, according to the methods of thepresent disclosure.

FIG. 1 shows a flow diagram for a method 100 for preparing CBG or a CBGanalog in accordance with the methods disclosed herein. The method 100comprises the following steps: combing (110) a compound (I) 10 withgeraniol 20 and a solvent 30 to form a reaction mixture 112; andcombining (120) the reaction mixture 112 with an acid catalyst 40 toform a product mixture 122 comprising the CBG or the CBG analog. Themethod 100 may further comprise a step of separating (130) the CBG orCBG analog 132 from the product mixture 122. The method 100 may furthercomprise a step of purifying (140) the separated CBG or CBG analog 132to provide a high purity CBG or CBG analog 142. The method 100 mayfurther comprise a step 150 of recovering at least a portion of thecompound (I) 10, at least a portion of the geraniol 20, or both. Therecovering may be from the product mixture 122 or from the mixture 134remaining after the separating step.

FIG. 2 shows a flow diagram for a method 200 for preparing a CBGA or aCBGA analog in accordance with the methods of the present disclosure.The method 200 comprises combining (210) CBG or a CBG homolog 60 withmethylmagnesium carbonate (MMC) 70 and a solvent 80 to provide a productmixture 212 comprising the CBGA or the CBGA homolog 222. The method mayfurther comprise a step of purifying (220) the product mixture 212 toprovide the CBG or CBG analog 222 in higher purity.

FIG. 3 shows a flow diagram for a method 300 for preparing CBGA or aCBGA analog in accordance with the methods of the present disclosure.The method 300 comprises the following steps: combining (310) a compound(II) 12 with geraniol 20 and a solvent 30 to form a reaction mixture312; combining (320) the reaction mixture 312 with an acid catalyst 40to form a first product mixture 322; and combining (330) at least aportion of the first product mixture 322 with one or more mildhydrolysis reagents 50 to provide a second product mixture 332comprising the CBGA or the CBGA analog. The method 300 may furthercomprise a step of separating (340) the CBGA or CBGA analog from theproduct mixture 332. The method 300 may further comprise a step ofpurifying (350) the separated CB G or CB G analog 342 to provide a highpurity CBG or CBG analog 352. The method 300 may further comprise a step360 of recovering at least a portion of the compound (II) 12, at least aportion of the geraniol 20, or both.

EXAMPLES Example 1

General reaction scheme for the synthesis of compositions comprisingCBG:

In a typical experiment, 5-pentylbenzene-1,3-diol (olivetol) and a molarexcess of (2E)-3,7-dimethyl-2,6-octadien-1-ol (geraniol) were combinedin a solvent. To this mixture was added an acidic catalyst. The reactionmixture was allowed to stir for a period of time at a temperature toproduce a product mixture comprising CBG or a CBG analog.

Example 2

The general procedure from Example 1 was used to study the effects ofgeraniol equivalents, catalyst equivalents, catalyst, solvent, reactiontemperature, and reaction time on CBG yield. The results fromexperiments are summarized in Tables 1 & 2.

TABLE 1 Preparation of Compositions Comprising CBG Olivetol GeraniolCatalyst Approximate (g, mmol) Equivalents Equivalents Catalyst SolventT (° C.) t (hours) CBG (w/w %) 1, 5.55 1.7 0.01 TsOH•H₂O CHCl₃ 20 14 201, 5.55 1.7 0.08 TsOH•H₂O CHCl₃ 20 14 20 1, 5.55 1.7 0.01camphorsulfonic CHCl₃ 20 14 18 acid 1, 5.55 1.7 0.1 camphorsulfonicCHCl₃ 20 14 19 acid 1, 5.55 2.6 0.01 TsOH•H₂O CHCl₃ 20 14 15 1, 5.55 3.50.01 TsOH•H₂O CHCl₃ 20 14 15 1, 5.55 1.7 0.01 TsOH•H₂O CHCl₃ 50 14 trace1, 5.55 1.7 0.01 TsOH•H₂O CHCl₃ 60 14 trace 1, 5.55 1.7 0.01 TsOH•H₂OCHCl₃ 20 38 18 1, 5.55 1.7 0.01 TsOH•H₂O Ethyl 20 14 0 acetate 1, 5.551.7 0.01 TsOH•H₂O Acetone 20 14 0 1, 5.55 1.7 0.01 TsOH•H₂O Ethanol 2014 0 1, 5.55 1.7 0.01 TsOH•H₂O TBME 20 14 10 1, 5.55 1.7 0.01 TsOH•H₂OHeptane 20 14 8

TABLE 2 Preparation of Compositions Comprising CBG Olivetol GeraniolApproximate (g) (1 eq.) Equivalents Catalyst (g) Catalyst Solvent T (°C.) t (hours) CBG (w/w %) 1.000 1.2  1.0 g Al₂O₃, acidic Brockman ICHCl₃ 66 24 8 0.252 1.2 0.252 g Al₂O₃, acidic Brockman I none 85 24 190.252 1.2 0.252 g Al₂O₃, acidic Brockman I CHCl₃:PhMe 1:1 85 24 23 0.1081.6 0.016 g/ TsOH•H₂O/Na₂SO₄ CHCl₃ 85 24 29 0.221 g 0.108 1.6  0.016TsOH•H₂O CHCl₃ 85 24 35 0.204 1.7 0.1 Fe(ClO₄)₃ nH₂O CHCl₃ RT 24 190.204 1.7  0.08 CF₃COOH CHCl₃ RT 24 1 0.204 1.7 0.1 camphorsulfonic acidCHCl₃ RT 24 26 0.204 1.7 0.20 mL/ BF₃•Et₂O/SiO₂ CHCl₃ RT 24 20 1.9 g0.204 1.7 0.204 g montmorillonite K10 CHCl₃ RT 24 21

Example 3

Olivetol (1 g, 5.55 mmol) was combined with geraniol (1.45 g, 9.44 mmol)in chloroform. To the mixture was added p-toluenesulfonic acidmonohydrate (0.055 mmol). The reaction mixture was stirred at roomtemperature for 14 hours. Normal phase flash chromatography with anacetone/heptane solvent system was performed to separate the CBG fromthe reaction mixture. High performance liquid chromatography (HPLC)demonstrated that the CBG was isolated in >97% purity (FIG. 4 ). The CBGwas further purified by crystallization from heptane to isolate CBG ascolourless crystals (25% yield).

Example 4

Olivetol (100 g, 555 mmol) was combined with geraniol (145 g, 944 mmol)in 4 L chloroform. To the mixture was added p-toluenesulfonic acidmonohydrate (5.5 mmol). The reaction mixture was stirred at roomtemperature in the dark for 14 hours. The mixture was washed thoroughlywith saturated aqueous NaHCO₃. The organic layer was washed with water,dried over anhydrous sodium sulfate, and the solvent removed at 40° C.under reduced pressure to give 250 g dark brown oil. A 30.8 g portion ofthis mixture was purified in the following way: batch fractionaldistillation under reduced pressure was used, to obtain 8.5 g amber oilcontaining CBG in approximately 40% wt/wt purity. During thedistillation, olivetol and geraniol were recovered in high purity. Thedistilled CBG was crystallized from heptane solution (1:2 w/w ratio) at−8° C. and the purified CBG was isolated as colourless crystals (1.7 g,—8% yield based on olivetol). HPLC chromatograms of the fractions fromdistillation are shown in FIGS. 5A-5E. Specifically, FIG. 5A shows achromatogram of a product mixture comprising about 20% CBG provided bythe methods disclosed herein. FIG. 5B shows a chromatogram of thedistillate obtained from the product mixture comprising about 40% CBG.FIGS. 5C and 5D show chromatograms of recovered geraniol and olivetol,respectively. FIG. 5E shows a chromatogram of CBG crystals afterseparation from the product mixture and crystallization.

Example 5

To a flask equipped with a magnetic stir bar, containing CBG (58 mg,0.183 mmol, 1.0 equiv.) was added a 2.0 M solution of methyl magnesiumcarbonate (0.505 ml, 1.01 mmol, 5.5 equiv.) in dimethylformamide (DMF)under CO₂ atmosphere. The mixture was heated to 120° C. and stirred for2.5 h. The mixture was cooled to room temperature, and carefullyquenched with an excess of a 10% wt solution of citric acid in water,and diluted with 5 ml methyl tert-butyl ether (MTBE). Once the solidswere fully dissolved, the organic layer was washed with 3×5 ml water,and the solvent evaporated under reduced pressure to give 118 mg pinksolid. HPLC analysis showed this solid contained 54% wt CBGA (˜85%yield), and 9% wt (FIG. 6 ).

Example 6

To a flask equipped with a magnetic stir bar, containing CBG (1.640 g,5.182 mmol, 1.0 equiv.) under CO₂ atmosphere was added a 2.0 M solutionof methyl magnesium carbonate (8.0 ml, 16 mmol, 3.1 equiv.) indimethylformamide (DMF). The mixture was heated to 120° C. and stirredfor 3 h. The mixture was cooled to room temperature, diluted with about15 ml of 1:1 MeOH:water, and carefully quenched with an excess of a 50%wt solution of citric acid in water. Once the solids were fullydissolved, the mixture was extracted with about 2×10 ml methyltert-butyl ether (MTBE), and the combined organic layers were washedwith 3×10 ml water. The solvent was evaporated under reduced pressure togive 2.046 g red-brown oil. The mixture was dissolved in heptane with afew drops of acetone, concentrated under reduced pressure to about 10 mlvolume, and crystallized slowly at 4° C. to yield 222 mg bright orangecrystals of CBGA. Concentrating the mother liquor produced a further 261mg light tan coloured crystals. HPLC analysis showed both crops ofcrystals to be pure CBGA (483 mg total, 25% isolated yield)

In the present disclosure, all terms referred to in singular form aremeant to encompass plural forms of the same. Likewise, all termsreferred to in plural form are meant to encompass singular forms of thesame. Unless defined otherwise, all technical and scientific terms usedherein have the same meaning as commonly understood by one of ordinaryskill in the art to which this disclosure pertains.

As used herein, the term “about” refers to an approximately +/−10%variation from a given value. It is to be understood that such avariation is always included in any given value provided herein, whetheror not it is specifically referred to.

It should be understood that the compositions and methods are describedin terms of “comprising,” “containing,” or “including” variouscomponents or steps, the compositions and methods can also “consistessentially of or “consist of the various components and steps.Moreover, the indefinite articles “a” or “an,” as used in the claims,are defined herein to mean one or more than one of the element that itintroduces.

For the sake of brevity, only certain ranges are explicitly disclosedherein. However, ranges from any lower limit may be combined with anyupper limit to recite a range not explicitly recited, as well as, rangesfrom any lower limit may be combined with any other lower limit torecite a range not explicitly recited, in the same way, ranges from anyupper limit may be combined with any other upper limit to recite a rangenot explicitly recited. Additionally, whenever a numerical range with alower limit and an upper limit is disclosed, any number and any includedrange falling within the range are specifically disclosed. Inparticular, every range of values (of the form, “from about a to aboutb,” or, equivalently, “from approximately a to b,” or, equivalently,“from approximately a-b”) disclosed herein is to be understood to setforth every number and range encompassed within the broader range ofvalues even if not explicitly recited. Thus, every point or individualvalue may serve as its own lower or upper limit combined with any otherpoint or individual value or any other lower or upper limit, to recite arange not explicitly recited.

Therefore, the present disclosure is well adapted to attain the ends andadvantages mentioned as well as those that are inherent therein. Theparticular embodiments disclosed above are illustrative only, as thepresent disclosure may be modified and practiced in different butequivalent manners apparent to those skilled in the art having thebenefit of the teachings herein. Although individual embodiments aredis-cussed, the disclosure covers all combinations of all thoseembodiments. Furthermore, no limitations are intended to the details ofconstruction or design herein shown, other than as described in theclaims below. Also, the terms in the claims have their plain, ordinarymeaning unless otherwise explicitly and clearly defined by the patentee.It is therefore evident that the particular illustrative embodimentsdisclosed above may be altered or modified and all such variations areconsidered within the scope and spirit of the present disclosure. Ifthere is any conflict in the usages of a word or term in thisspecification and one or more patent(s) or other documents that may beincorporated herein by reference, the definitions that are consistentwith this specification should be adopted.

Many obvious variations of the embodiments set out herein will suggestthemselves to those skilled in the art in light of the presentdisclosure. Such obvious variations are within the full intended scopeof the appended claims.

1. A method for preparing cannabigerolic acid (CBGA) or a CBGA analog,the method comprising: reacting geraniol with a compound (I) of thefollowing structure:

wherein R¹ is hydrogen, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl,(OCH₂CH₂)₀₋₆O(C₁-C₈ alkyl), (C₀-C₄ alkyl)-NR^(2a)R^(2b), (C₀-C₄alkyl)-aryl, (C₀-C₄ alkyl)-heteroaryl, (C₀-C₄ alkyl)-cycloalkyl, or(C₀-C₄ alkyl)-heterocycloalkyl, wherein R^(2a) and R^(2b) are eachindependently hydrogen or C₁-C₆ alkyl; in the presence of an acidcatalyst and optionally a solvent to form CBG or a CBG analog, whereinthe acid catalyst is camphorsulfonic acid, acidic alumina,montmorillonite K10, iron (III) perchlorate hydrate, or a combinationthereof; and reacting the CBG or CBG analog with methylmagnesiumcarbonate to provide the CBGA or CBGA analog.
 2. The method of claim 1,wherein the acid catalyst is acidic alumina.
 3. The method of claim 1,wherein the acid catalyst is camphorsulfonic acid.
 4. The method ofclaim 1, wherein the acid catalyst is montmorillonite K10.
 5. The methodof claim 1, wherein the acid catalyst iron (III) perchlorate hydrate. 6.The method of claim 1, wherein the compound (II) and geraniol arepresent in a compound (II):geraniol molar ratio of between 10:1 and1:10.
 7. The method of claim 1, wherein R¹ is C₁-C₁₂ alkyl.
 8. Themethod of claim 1, wherein R¹ is C₃H₇ or C₇H₁₅.
 9. The method of claim1, wherein R¹ is C₅H₁₁.
 10. The method of claim 1, wherein the reactingstep is performed with heating.
 11. The method of claim 1, wherein thesolvent is present.
 12. The method of claim 11, wherein the solvent ischloroform, heptane, tert butylmethyl ether, diethyl ether,dichloromethane, dichloroethane, trifluorotoluene, hexane, cyclohexane,pentane, toluene, or any combination thereof.
 13. A method for preparingcannabigerolic acid (CBGA) or a CBGA analog, the method comprising:reacting geraniol with a compound (II) of the following structure:

wherein R¹ is hydrogen, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl,(OCH₂CH₂)₀₋₆O(C₁-C₈ alkyl), (C₀-C₄ alkyl)-NR^(2a)R^(2b), (C₀-C₄alkyl)-aryl, (C₀-C₄ alkyl)-heteroaryl, (C₀-C₄ alkyl)-cycloalkyl, or(C₀-C₄ alkyl)-heterocycloalkyl, wherein R^(2a) and R^(2b) are eachindependently hydrogen or C₁-C₆ alkyl; in the presence of an acidcatalyst and optionally a solvent, wherein the acid catalyst iscamphorsulfonic acid, acidic alumina, montmorillonite K10, iron (III)perchlorate hydrate, or a combination thereof; and hydrolyzing with oneor more mild hydrolysis reagents to provide the CBGA or CBGA analog. 14.The method of claim 13, wherein the compound (II) and geraniol arepresent in a compound (II):geraniol molar ratio of between 10:1 and1:10.
 15. The method of claim 13, wherein R¹ is C₁-C₁₂ alkyl.
 16. Themethod of claim 13, wherein the reacting step is performed with heating.17. The method of claim 13, wherein the solvent is present.
 18. Themethod of claim 17, wherein the solvent is chloroform, heptane, tertbutylmethyl ether, diethyl ether, dichloromethane, dichloroethane,trifluorotoluene, hexane, cyclohexane, pentane, toluene, or anycombination thereof.
 19. A method for preparing cannabigerolic acid(CBGA) or a CBGA analog, the method comprising: reacting geraniol with acompound (II) of the following structure:

wherein R¹ is hydrogen, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl,(OCH₂CH₂)₀₋₆O(C₁-C₈ alkyl), (C₀-C₄ alkyl)-NR^(2a)R^(2b), (C₀-C₄alkyl)-aryl, (C₀-C₄ alkyl)-heteroaryl, (C₀-C₄ alkyl)-cycloalkyl, or(C₀-C₄ alkyl)-heterocycloalkyl, wherein R^(2a) and R^(2b) are eachindependently hydrogen or C₁-C₆ alkyl; in the presence of acidic aluminaand a solvent, wherein the compound (II) and geraniol are present in acompound (II):geraniol molar ratio of between 10:1 and 1:10; andhydrolyzing with one or more mild hydrolysis reagents to provide theCBGA or CBGA analog.
 20. The method of claim 19, wherein the reactingstep is performed with heating.
 21. The method of claim 19, wherein thesolvent is chloroform, heptane, tert butylmethyl ether, diethyl ether,dichloromethane, dichloroethane, trifluorotoluene, hexane, cyclohexane,pentane, toluene, or any combination thereof.
 22. The method of claim19, wherein R¹ is C₁-C₁₂ alkyl.